Cancer patients are at an increased risk of venous thromboembolism. There have been several guidelines published on the topic from the American College of Chest Physicians (ACCP), the American Society of Clinical Oncology (ASCO), and the National Comprehensive Cancer Network (NCCN). Although they agree on some issues regarding prophylaxis and treatment there are several areas that vary. This presentation covers the varying recommendations and the areas of consensus (yellow boxes) among the guidelines while using a patient case to guide their interpretation.
3. Goals
Understand risk of VTE associated with cancer
Take away where the consensus lies among
guidelines
Identify gray areas regarding prophylaxis and
treatment of VTE in cancer patients
4. Patient Case
Ms. M is a 43 y/o female with cervical cancer
diagnosed 2 years ago
Undergone 4 lines of chemotherapy with progressive
disease and painful lymphadenopathy
TIL harvest surgery – L groin mass 2 months ago
Admitted for TIL therapy:
Chemo -> T-cells -> IL-2 -> Supportive Care
PMH: Diabetes, HTN, PE (1 year ago)
Allergies: Aspirin
Relevant Labs
BMI
47.5 kg/m2
WBC
5.29 x 109/L
Hgb
10.3 g/dL
Platelets
306 x 109/L
14. Nonsurgical VTE Risk
Padua Prediction Score
Risk Factor
Points
Active Cancer
3
Previous VTE (excluding SVT)
3
Reduced mobility*
2
Already known thrombophilic condition
1
Recent (≤ 1 mo.) trauma/surgery
1
Elderly age (≥ 70y)
1
Heart and/or respiratory failure
1
Acute MI or ischemic stroke
1
Obesity (BMI ≥ 30)
1
Ongoing hormonal treatment
1
*Anticipated bed rest with bathroom privileges for at least 3 days
15. Surgical VTE Risk
Roger
Operation type
Thoracic area highest risk
Cancer
Disseminated cancer
Chemo within 30 days
Caprini
Recent Stroke (<1 mo.)
History of VTE
Age
Malignancy
BMI
17. Multiple Myeloma
Low Risk
High Risk
Thalidomide or Lenalidomide
therapy
Thalidomide or Lenalidomide
therapy in combination with:
High dose dexamethasone
Doxorubicin
Multiagent chemo
PLUS
0-1 risk factor for VTE
Thalidomide or Lenalidomide
therapy
PLUS
≥ 2 risk factors for VTE
Aspirin 81-325 mg once daily
LMWH
OR
Full dose warfarin (INR 2-3)
18. Khorana Score
Patient Characteristic
Risk Score
Site of Primary Cancer
Very High Risk (stomach, pancreas)
High Risk (lung, lymphoma, gynecologic, bladder,
testicular)
2
1
Prechemotherapy platelet count ≥ 350 x 109/L
1
Hgb < 10 g/dL
1
Prechemotherapy leukocyte count ≥ 11 x 109/L
1
BMI 35 kg/m2
1
Total Score
0
1-2
3 or higher
Risk of Symptomatic VTE
Low (0.8-3%)
Intermediate (1.8-8.4%)
High (7.1-41%)
22. Consensus Summary
Inpatient prophylaxis should consist of
prophylactic doses of LMWH, UFH, or
Fondaparinux
Outpatient prophylaxis should be done:
In multiple myeloma patients undergoing therapy
with thalidomide or lenalidomide
As an extension of inpatient surgical prophylaxis for
high risk abdominal or pelvic surgeries
Treatment of DVT/PE should be done using LMWH
rather than Warfarin
23. Gray Areas
Who should receive prophylaxis as an inpatient?
Should outpatients at high risk for VTE receive
prophylaxis based upon the Khorana score?
What is the appropriate length of therapy for
VTE/PE in the cancer patient?
What factors impact extension of therapy beyond 36 months?
24. Future Directions for
Research
Determine which cancer patients benefit most
from thromboprophylaxis:
Risk stratification tools
Specific cancer types
Identify better biomarkers
Determine ideal duration of anticoagulation:
Prophylaxis - Risk related to time from diagnosis
Treatment - Need for extended therapy
25. Patient Case
Ms. M is a 43 y/o female with cervical cancer
diagnosed 2 years ago
Undergone 4 lines of chemotherapy with progressive
disease and painful lymphadenopathy
TIL harvest surgery – L groin mass 2 months ago
Admitted for TIL therapy:
Chemo -> T-cells -> IL-2 -> Supportive Care
PMH: Diabetes, HTN, PE (1 year ago)
Allergies: Aspirin
Relevant Labs
BMI
47.5 kg/m2
WBC
5.29 x 109/L
Hgb
10.3 g/dL
Platelets
306 x 109/L
26. Patient Case
Ms. M has a Padua score of 7 indicating she is at
high risk for VTE
According to ACCP and NCCN she should receive
prophylaxis as an inpatient:
Enoxaparin 40mg SQ Qday
UFH 5,000 units SQ Q8H
Fondaparinux 2.5 mg SQ Qday
Upon discharge, should she continue
prophylaxis?
Intermediate Khorana Risk
27. References
1. Akl EA, Labedi N, Barba M et al. Anticoagulation for the long-term treatment of venous thromboembolism in patients with cancer.
Cochrane Database Syst Rev. 2011;(6):CD006650. doi(6):CD006650.
2. Gould MK, Garcia DA, Wren SM et al. Prevention of VTE in nonorthopedic surgical patients: Antithrombotic therapy and
prevention of thrombosis, 9th ed: American college of chest physicians evidence-based clinical practice guidelines. Chest.
2012;141(2 Suppl):e227S-77S.
3. Kahn SR, Lim W, Dunn AS et al. Prevention of VTE in nonsurgical patients: Antithrombotic therapy and prevention of thrombosis, 9th
ed: American college of chest physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 Suppl):e195S-226S.
4. Khorana AA. Cancer-associated thrombosis: Updates and controversies. Hematology Am Soc Hematol Educ Program.
2012;2012:626-30.
5. Lyman GH, Khorana AA, Kuderer NM et al. Venous thromboembolism prophylaxis and treatment in patients with cancer:
American society of clinical oncology clinical practice guideline update. J Clin Oncol. 2013;31(17):2189-204.
6. Palumbo A, Rajkumar SV, Dimopoulos MA et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma.
Leukemia. 2008;22(2):414-23.
7. Semchuk WM, Sperlich C. Prevention and treatment of venous thromboembolism in patients with cancer. Can Pharm J (Ott).
2012;145(1):24,29.e1.
8. Streiff MB, Bockenstedt PL, Cataland SR et al. Venous thromboembolic disease. J Natl Compr Canc Netw. 2013;11(11):1402-29.
PE treated with LMWH transitioned to warfarin – had difficulty maintaining therapeutic INR, completed unclear from patient’s record how long she underwent treatmentAspirin – tight throat
VTE is the formation of a clot in the veins and can occur in the deep veins of the leg, this can lead to disruption of blood flow and swelling of the leg -> Can also lead to PE through the formation of an embolus which then travels back to the heart via pulmonary veins. Can have a major impact on morbidity and mortality – if untreated would have 30% mortality rateCan also include superficial venous thrombosis and splanchnic venous thrombosis, but those will not be the focus of the talk today.
First to recognize the connection between cancers and clottingSuperficial thrombophlebitis (blood clot under surface of skin) was associated with a diagnosis of abdominal cancer Trousseau’s signLater in life - diagnosed this same sign in himself and subsequently died of pancreatic cancer
Health Claims database analysis found that of solid tumor ambulatory patients undergoing chemo 12.6% (8-19% depending on tumor type) had VTE within the 12 months following chemo initiation; 80% of VTE in cancer patients occur in the outpatient setting Non- cancer patients were a gender and age matched population from the health claims database2nd leading cause of death in cancer patients
There are many factors that contribute to the pathophysiology of thrombosis in cancer patients. Vessel compression by tumor and increased exposure to surgical procedures are factorsAnother evolving theory is the release of Procoagulants by tumor cells, specifically tissue factorProcoagulants Tissue FactorVessel wall stasisDirect vessel compressionImmobilizationSurgical ProceduresChemotherapy
Cancer types at higher risk – metastatic; brain, pancreas, stomach, bladder, gynecologic, lung, lymphoma, myeloproliferative, kidneyChemotherapy – Thalidomide/Lenolidamide, tamoxifene/raloxifene
Luckily or unluckily – there are several guidelines which have evaluated studies of thrombosis in CA patients
ACCP – Nonsurgical inpatients who are high risk should get prophylaxis and risk is defined by the padua prediction scale. Surgical inpatients may or may not require prophylaxis depending upon what type of surgery they have undergone and what their underlying risks are. Risk is determined by the roger or caprini score which determines the need for pharmacologic agent, then surgical site alters when is should be administered. For example, a patient undergoing craniotomy or spinal surgery should only be pharmacologically prophylaxed if they are high risk and should not be prophylaxed until hemostasis is established.# Surgical patient risk of VTE dependent upon Rogers/Caprini score*High risk VTE patients undergoing abdominal or pelvic surgery for cancer
Patients were followed for symptomatic VTE for 90 days – VTE occurred in 11% of high risk patients who did not receive prophylaxis compared to 0.3% of low risk patients. ACCP acknowledges that this score is not ideally validated, but provides the best available basis for analyzing a medical patient’s baseline risk. Note – patients at a low risk of thrombosis should not undergo prophylaxis pharmacologically or mechanically.
Roger - Operation type dictates score most, with cancer contributing a few points and other biomarkers and general physical health can also contributeCaprini – History weighted more heavily along with, then comes age and malignancy is included in the risk score as well.Cancer in either of these scoring systems only contributes moderately to the overall risk and would not on it’s own make the patient a high risk patient.
4 weeks post op for high risk patients undergoing abdominal or pelvic surgeries. ACCP – other risk factors for VTE include: previous VTE, immobilization, hormonal therapy, angiogenesis inhibitors, thalidomide, and lenalidomide. Specifically mention that if Cancer is only risk factor:No prophylaxis andCancer plus indwelling CVC: No prophylaxisIn patients with cancer heparin slightly decreased mortality at 2 years, significantly reduced symptomatic VTE, but failed to determine beneficial or detrimental effects on major and minor bleeding or quality of life. Use of warfarin in cancer patients with no other indication for prophylactic anticoagulation had no significant effect on mortality up to 5 years out and increased the risk of major (RR 4.24) and minor (RR 3.34) bleeding while providing a RR reduction of 85% (RR 0.15; 95% CI 0.02-1.2) on VTE. Risk of bleeding outweighed impact on VTE for warfarin. Benefit of prophylaxis in CVC is unclear
Thalidomide + Dex without prophy => 26% rate of VTEACCP recommends patients undergoing this therapy receive LMWH or LDUH as opposed to no prophylaxis, but don’t mention this specific risk classification, nor the use of ASA.ASCO recommends ASA or LMWH for low risk patients and LMWH for high risk patients. No mention of warfarin.No prospective randomized trials have been done to validate the use of this recommendation in decreasing the risk of thromboembolism in patients with multiple myeloma. Instead, this risk stratification was constructed through ‘common sense’ on the topic and expert consensus. Evaluated available literature to find “safest and least cumbersome form of thromboprophylaxis that reduces risk of VTE at least below 10%” Although there were some cases where LMWH was not effective according to this definition, the majority of studies showed that both LMWH and full dose warfarin were effective. Authors state these recommendations should not be considered firm guidelines.VTE is most likely to happen within the first 12 months of diagnosis in cancer patients and within the first 6 months for myeloma, may consider limiting prophylaxis duration in the future. No studies exist to evaluate thromboprophylaxis in patients with recurrent disease, although incidence of VTE in lower in recurrence.
If provoked DVT patient should be evaluated after 3 months for continued risk/benefit of ongoing therapy
Assumed risk = median control group risk across studiesCorresponding risk = based on assumed risk in the VKA group and the relative effect of the interventionNote – No difference in mortality rate or major/minor bleeding was found.
PE treated with LMWH transitioned to warfarin – had difficulty maintaining therapeutic INR, completed unclear from patient’s record how long she underwent treatmentAspirin – tight throat
